Alzheimer's disease (AD) is the most common cause of dementia in the aged population. The accumulation of large numbers of senile plaques containing the 40-42 amino acid amyloid .beta. protein (A.beta.) is a classic pathological feature of AD. Both genetic and cell biological findings suggest that the accumulation of A.beta. in the brain is the likely cause of AD (Yankner, B. A. (1996) Neuron 16, 921-932.; Selkoe, D. J. Science 275, 630-631 (1997)). Strong genetic evidence in support of the pathogenic role of A.beta. came from the observation that individuals who inherit mutations in the amyloid precursor protein almost invariably develop AD at an early age. These mutations increase the production of a long variant of the A.beta. peptide that forms senile plaques in the brain (Goate et al., (1991) Nature 349, 704-706). Mutations and allelic variations in other genes that cause AD, including the presenilins and apolipoprotein E, also result in increased production or deposition of the A.beta. peptide. Reiman, et al. (1996) N.E.J.Med. 334, 752-758, reported that in middle age, early to mid 50's, individuals who are homozygous for the Apo E4 gene have reduced glucose metabolism in the same regions of the brain as in patients with Alzheimer's disease. These findings suggest that the pathological changes in the brain associated with this gene start early. Furthermore, individuals with Down's syndrome overexpress the amyloid precursor protein, develop A.beta. deposits in the brain at an early age, and develop Alzheimer's disease at an early age. Finally, the A.beta. protein has been demonstrated to be highly toxic to nerve cells. Thus, it is widely believed that drugs which decrease the levels of A.beta. in the brain would prevent Alzheimer's disease.
The known genetic causes of AD can account for only a small proportion of the total number of cases of AD. Most cases of AD are sporadic and occur in the aged population. A major goal of research is the identification of environmental factors that predispose to AD that would be amenable to therapeutic measures.
It is therefore an object of the present invention to provide methods for predicting populations at risk of developing AD.
It is another object of the present invention to provide diagnostics and pharmaceuticals to decrease the production of amyloid .beta. protein (A.beta.), and thereby to prevent or reduce the liklihood of developing AD.
It is a further object of the present invention to provide pharmaceutical treatments to treat AD in patients' having the neuropsychiatric or diagnostic criteria for AD.